Lyme disease is a multisystem disorder caused by infection with the tick-borne spirochete, Borrelia burgdorferi. The disease occurs in stages that reflect the biology of the spirochete as it adapts from survival in the tick to the more hostile environment of the mammal. B. burgdorferi contains an abundant array of highly immunogenic outer membrane lipoproteins (Osps) that are differentially expressed throughout the spirochete lifecycle. Lipoproteins incite inflammation and are believed to be the principal spirochete component causing disease. Lipoproteins can also elicit protective humoral immunity but current vaccines fail to elicit long-lived immunity. This proposal is based on our novel findings that absence of CD1d, a non-classical antigen-presenting molecule that binds lipid Ag, renders mice susceptible to B. burgdorferi infection and disease. Pathology correlates with high-titer T-dependent antibody responses to spirochete lipoproteins, including lipoproteins only transiently expressed by spirochetes establishing infection in the host. We hypothesize that CD1d functions to facilitate the elimination of spirochetes and their disease-inciting lipoproteins by potentiating innate immune mechanisms. This proposal seeks to 1) understand the molecular and cellular mechanisms by which CD1d-mediated immunity controls spirochetal pathogens; 2) determine whether blocking CD1d will enhance the duration of lipoprotein vaccine-induced immunity; 3) examine the evolution of B. burgdorferi infection in the absence of CD1d, and effects the early strong adaptive immune response has on spirochetes that persist in the host; and 4) use the adaptive immune response that evolves in the absence of CD1d to identify key lipoproteins necessary for tick-borne spirochetes to infect and disseminate in the mammalian host. The completion of these studies will allow for broad insights into the role of CD1d in host defense against pathogens and clearance of their proinflammatory lipoprotein antigens that incite disease. In addition, these studies may suggest feasible strategies to improve vaccination-induced protective immunity. For the field of Lyme disease, defining the key molecules expressed by tick-borne spirochetes will move us one step closer toward understanding how this pathogen invades, disseminates and persists in the mammalian host.